Cancer is one of the leading causes of death in the developed world, with over one million people diagnosed with cancer and 500,000 deaths per year in the United States alone. Overall it is estimated that more than 1 in 3 people will develop some form of cancer during their lifetime.
Folate Receptor 1 (FOLR1), also known as Folate Receptor-alpha (FRα), or Folate Binding Protein, is a glycosylphosphatidylinositol (GPI)-anchored glycoprotein with a strong binding affinity for folic acid and reduced folic acid derivatives (see Leung et al., Clin. Biochem. 46:1462-1468 (2013)). FOLR1 mediates delivery of the physiological folate, 5-methyltetrahydrofolate, to the interior of cells. Expression of FOLR1 on normal tissues is restricted to the apical membrane of epithelial cells in the kidney proximal tubules, alveolar pneumocytes of the lung, bladder, testes, choroid plexus, and thyroid (Weitman S D, et al., Cancer Res. 52:3396-3401 (1992); Antony A C, Ann. Rev. Nutr. 16:501-521 (1996); Kalli K R, et al., Gynecol. Oncol. 108:619-626 (2008)). FOLR1 is overexpressed in epithelial-derived tumors including ovarian, uterine, breast, endometrial, pancreatic, renal, lung, colorectal, and brain tumors. This expression pattern of FOLR1 makes it a desirable target for FOLR1-directed cancer therapy.
Vascular endothelial growth factor-A (VEGF), also known as vascular permeability factor (VPF), is the prototype member of the VEGF family of proteins and a key regulator of angiogenesis (Hoeben et al., Pharmacol. Rev. 56:549-580 (2004); Ferrara et al., Nat. Med. 9:669-676 (2003)). Angiogenesis is the process of new blood vessel development from pre-existing vasculature and is important for at least wound healing, organ regeneration, and the female reproductive system (Hoeben et al., supra; Ferrara et al., supra). Angiogenesis is also important for several pathological processes including tumor development, growth, and metastasis (Hoeben et al., supra; Ferrara et al., supra). VEGF is a proangiogenic factor highly expressed in normal lung, kidney, heart, adrenal gland, liver, spleen, and gastric mucosa tissues and highly expressed in many human tumors (Hoeben et al., supra). Its elevation or misexpression in tumors and proangiogenic function make VEGF a desirable target for targeted cancer therapy.
Cisplatin and carboplatin, which are platinum analogues and alkylating chemotherapeutic agents, have been used alone or in combination with other agents for the treatment of a variety of solid tumors for decades (Lokich et al., Annals. Of Oncology 9:13-21 (1998)). Carboplatin has been reported as having reduced gastrointestinal effects as compared to cisplatin (Lokich et al.). However, carboplatin causes the negative side effect of suppressing bone marrow (Lokich et al.). Thus, improved efficacy and tolerability of treatments with cisplatin and carboplatin are desirable.
Doxorubicin, an anthracycline antibiotic chemotherapy agent, has also been used as a treatment for a variety of cancers alone or in combination with other chemotherapeutic agents such as paclitaxel (a mitotic inhibiting chemotherapeutic agent referred to as TAXOL® (Bristol Myers Squibb), see also Gehl et al., Annals of Oncology, 7:687-639 (1996)). The utility of doxorubicin as a cancer treatment is limited by its toxicity, in particular, doxorubicin's cardiotoxicity (see Tacar et al., J. of Pharmacy & Pharmacology, 65: 157-170 (2013)). Thus, improved efficacy and tolerability of treatments with doxorubicin are also desirable. A liposome-encapsulated form of the hydrochloride (HCL) salt of the doxorubicin has also been developed. Liposomal delivery of doxorubicin HCL improves drug penetration into tumors and decreases drug clearance, thereby increasing the duration of therapeutic drug effects. A liposomal formulation of doxorubicin also modulates toxicity, specifically the cardiac effects commonly seen with anthracycline antitumor drugs.
The United States Food and Drug Administration (FDA) approved the combination treatment of bevacizumab (an anti-VEGF antibody referred to as AVASTIN® (GENENTECH, INC.)) with carboplatin and paclitaxel as a first-line treatment of advanced, recurrent nonsquamous non-small cell lung cancer (NSCLC) (see Cohen et al., Oncologist 12:713-718 (2007)). The combination of carboplatin and paclitaxel (CP therapy) was the previous first-line treatment of NSCLC (Sandler et al., N. Engl. J. of Medicine 355:2542-2550 (2006)). But while the addition of bevacizumab to the CP therapy increased patient survival benefit, this triple-combination (BV/CP) therapy resulted in increased treatment-related deaths and a higher incidence of both nonhematologic and hematologic adverse events (Cohen et al., supra at Tables 4-5). More recently, bevacizumab has also been approved in combination with chemotherapeutic agents for the treatment of cervical cancer, platinum-resistant recurrent epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer.
There remains an unmet medical need for more effective therapies, e.g., combination therapies targeting FOLR1 expressing tumor cells, for the treatment of cancers.